CA1270714A - Multicompartmentalized dermal and transdermal patches - Google Patents

Abstract

4-15684/+/CGC 1168 MULTICOMPARTMETALIZED DERMAL AND
TRANSDERMAL PATCHES

Abstract of the Disclosure A dermal or transdermal patch comprising (1) a backing layer which is non-permeable with respect to a drug formulation to be contained within the patch, (2) a membranous layer, which is permeable to the drug, having a first surface partially in contact with said backing layer so as to define multiple compartments, (3) at least one drug or drug formulation contained within said compartments, (4) an adhesive layer on a second surface of said membranous layer, and (5) a peelable protective cover layer on said adhesive layer.

Description

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In recent years, patches for delivering drugs for systemic absorption through the skin ~transdermalJ have become increasingly important. As experienced with this means of drug delivery has grown, i-t has been recognized that a grea~er and greater number of systemically active drugs can be administered via the transdermal route. A
good deal of the importance of this means of administra-tion resides in the fact that drugs can be delivered to the bloodstream without traversing the gastro-intestinal tract and avoiding a first pass through the hepatic system prior to reaching the target site. At the same time, transdermal medication can obtain these benefits without requiring a pro~essional to administer the drug.

Since self-administration is generally involved, patient compliance with application-instructions and the ability of the product to remain unchanged from the time of manufacture take on greater importance than otherwise.
Increasing physical changes in the distribution--o the active ingredients and vehicle over the product shelf-life (especially as with respect to coverage of the patch sur~ace area in a uniorm manner), require a greater degree o care and attention by the patient or other person administering the patch. This is a particular problem with those patches having a permeable membrane through which an active agent moves from an enclosed space within the patch to the skin.

In such a system (one of the types described in U.S.
Patents 3,996,934; 3,797,494; 3,742,951; and 3,598,122) the drug or drug formulation is generally contained within "',,, ' ' , ., . ~-:

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a "sack" formed from a non-porous backing material and a porous membranous layer. On the "outer" sur~ace of the membranous layer is a coating of an adhesive, which is ~urther covered by an occlusive protecting layer. The protecting layer is removed by the patient or person administering the patch immediately prior to applying the patch to the skin.

Frequently, the dermal and transdermal patches described above suffer from the defect that the drug or drug formulation contained within the "sack~ sinks or migrates to the bottom, i.e. when the patch is stored in an "on edge" orientation - a common storage position by those in the chain of distributi~n of the product as well as by patients. This is particular~y evident when patches having -a drug reservolr (one~sided) surface area of about 30cm2 or larger.- Hence, when the patch is to be applied, the user must insure-that the drug fo~mulation is evenly spread over the entire available surface area of the "sack" interior. Unfortunately, not all patients or those applying the patch can be relied upon to recognize the defect and to properly correct it.

Furthermore, unless the defect is properly remedied, the rate of transference of the drug from the patch to the skin will be significantly altered from that intended.
Some portions of the skin will b~ undermedicated.
When the desired delivery rate exceeds the skin's absorption rate, a significant portion of the drug may be wasted fran the acumulation of migrated drug~ When the intended delivery rate i~ less than the skin absorption rate, undermedicated area~ will receive less than the intended dose. ~he p~tient receives improper treatment.

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Another problem involving patches having active drug formulations which are semi solid or liquid, or become so at body tempexature, is similar drug formulation migration while the patch is being worn, especially with larger sizes designed for application to the trunk and other body parts which will be in a vertical posi-tion for an extended period. Here it is very unlikely that the patient will even be aware that a problem exists, let alone correct it.

It is an object of this invention to provide dermal and transdermal patches of the "sack" type which overcome these defects.

Another object of this invention is to provide dermal and transdermal patches in which patient interaction with the patch is reduced to removin~ the protective layer and applying the patch, without concern for any drug formulation migration therein.

A further object of the lnvention is to provide dermal and trans~ermal patches which can be stored in any orientation without concern.

A still further object of the invention is to allow the use of drug vehicles in "sack type" transdermal patches which have hitherto been unsuitable therefor.

Surprisingly, these objects, and others, have been achieved by compartmentaliziny the "sack" area containing the drug or formulation into a number of smaller, distinct "sacks" or compartments.

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The patches of the invention will be better under-stood with reference to the drawings in which like referenced numerals indicate like parts. Of course these drawings are exemplary only and do not limit the scope of the invention to the embodiments shown therein.

Brief Description of the Drawings Figures 1 and 3 are top views of two prior art patch embodiments.

Figures 2 and 4 are cross-sections of a typical prior art patch.

Figures 5-8 are top views of 4 embodiments of the invention.

Figures 9-12 are various views of Figure 8.

Figures 13, 14 and 15 are various views of a four compartment system analogous to Figures 8, 10 and 11.

Figure 16 is identical to Figure 10 except that the compartments do not contain the identical substance and/or concentration.

Figure 17 is a cross section of a "fold-over" embodi-ment of the invention before use.

Figure 18 is the embodiment of Figure 17 after folding.

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Figure 19 is a top view of a "back-up reserve" or "superloaded" compaxtment embodiment.of the invention.

Figure 20 is a cross section of Figure 19 along line 20-20.

Detailed Description of the Invention The instant invention is an improved dermal or trans-dermal patch having a drug or drug formulation contained within a drug compartment area adapted to be applied directly to the skin of a patient to be treated with the drug. The improvement resides primarily in splitting the drug reservoir 2 in Figures 1-4 into multiple compartments 8, as seen in Figures 5-17.

With reference to Figures 1-4, the previously known patches of this type are comprised of an occlusive protective backin~ layer 3, a permeab~e porous membrane 4 thereon orming therewith a total reservoir area 2, an adhesive layer 5 on the surface of porous membrane 4 (which adhesive layer is remote from the interior of reservoir 2 and backing layer 3), and an occlusive, removahle layer 6.on adhesive 5. The adhesive layer 5 may be over the entire surface of reservoir 2, as shown in Figure 2.or define an adhesive free area.21 (see Figure 4) over the reservoir. As seen from Figures 5-16, the invention is a patch except that the reservoir 2 has been broken up into a number of distinct compartments 8 by seals 9. Tab 7 is not shown in Figures 5, 6.and 7.

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The size of each compartment 8 should not exceed 33cm2, preferably 26.7c~2, more preferably 20cm2, most preferably 13.3 cm2. The maximum distance between the center of gravity lO (see Fig . 5 ) of a compartment and any ~order 20 of that compartment should not exceed 2.70cm, prefera~ly 2.55cm, more preferably 2.23cm, most preferably 1. 78cm, and the perimeter of the compartment ~hould not exceed 4.04 times the square root of the compartment area. While there is no concern over the compartment shape, the latter two limitations above do not apply if compartments are bounded by (a) arcs of concentric circles tsee Fig. 6) or (b) are poly~onal or of indiscriminate in shape and can be inscribed within a rectangle having a smaller perimeter.

Preferred patch shapes, exclusive.of tab 7 (used as a 2oint from which the user can.remove the prote.ction layer), are: oval, elliptical, circular, and rectangular or rectangular-like but having 2 arcuate ~nds opposite one another (see Fig. 8), although other shapes can also be used. Of these, circular and rectangular-like but having 2 substantially ~emi-circular opposing ends are more preferred and circular is most preferable.

The boundaries between adjaeent compartments (th0 inter compartment seals 9~ 12 ~nd 13), can be of any orientation; however, straight lines ~xtending radially outward from the center of gravity of the entire patch or frcm the cen~er o~ a cîrcle7 a port~on of ~hich fon~s more than ~ tangential portion of the outer perimeter of the medica~ion containin9 surface area of the patch are preferred. Also preferred are vertical or h~rizo~t~l `: " ~ . - '' , ~270~

~orders, especially a crosshatch pattern. Of course, combinations of Ya~ious types are also suiCable, especially in the case wherein concentric circles form some of boundaries of some of the compartments.

An additional advantage of compartmentalization of the patch is the a~ility to vary the drug vehicle to an extent heretofore impossible to accomplish. More fluid vehicles than the currently used viscous ointments can now be effectively utilized. This means that the pr~sent invention allows one to flexibly utilize drug ~ormulations giving a greater range of release rates ~nd more precisely control drug delivery to the skin. In effect, the instant invention allows ons to utilize any vehicle which ~1) will release the drug to the porous membraneous layer 4 and ~2) does not adversely interact with membranous l~yer ~ or backing layer 3.

.~ still further advantage of this invention is the ability to regulate drug delivery by the si~ple means of having (1) different concentrations of drug in different compartments, (2) different vehlcles having different drug release rates in differ~nt compartments~ ~3) additives such as flux enhancers in some, but not all co~partments, and~or (4) having diferent material5, haYin~ different drug transference rate5, f~rming the ~e~branous layer o dif~erent compartments. Also, different adhesiv~
coatings 5 on the membranous layer 4 o~er different compar~ments 8 ~ay be utilized to alter drug delivery~
Via any of these means the drug deli~ery rate of the overall patch can be more preci~el~ re9ulated ao as o y;eld ~che desired controlled, reliabl~, reproduc¢able resul t~, . .

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Of course, one can also load different compartments 8 with different drugs that are desirable to be administered simultaneously, stepwise, or any other precisely regulated manner. Such a system virtually eliminates problems of patient compliance as only a single patch need be applied. This system also permits the coadministration or precisely tailored administration of two or more drugs, which are incompatible with each other or the vehicles used, in a single patch.

The new patches can also be used to create a new means of sustained release administration of a drug. For example, in a three compartment patch, as in Figures 19 and 20, of two compartments have a first concentration of a drug and the third compartment has a much higher concen-tration, then via a burstable non-permeable (to drug) membrane 13 (which is burst just prior to or during application of the patch), and optionally a permeable non-bursting membrane 12, forming the seal between the low concen~ration and high concentration compartments, with a non-porous membrane 1~ covering the high concentration compartment instead of or in addition to the porous membranous layer 4, the high concentration compartment acts as a high load reserve to maintain the concentration of drug in the low concentration compartment at an appropriate level for a much longer period. When the non porous membrane is not used, the difference in transference rates and absorption rates due to the different concentrations can be exploited to obtain an initial loading dose with subsequent decrease to typical maintenance levels.

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,~ore specifically, with the application of certain drugs, particularly nitroglycerine, it is advantageous to administer the drug at one rate for a set perlod and at a lower rate for an additional period.

Such a scheme has not been practical using a single reservoir compar~nent patch. However with multi-compartment patches having different concentrations of drug in different compartments such a drug dose regimen can easily be obtained.

If a patch having 25~ of theoretical nitroglycerine loading in each of two compartments of equal size and a third compartment of the same size having 100~ of theoretical nitroglycerine loading is ad~inistered, for 16 hours the patient is receiving a loading dose. Over this time the ~w dose compartments have been essentially depleted, yet the high dose compartment still has a subst~ntial amount of drug remaining; ~n ~mount sufficient to deliver a therapeutic level o~ medication for the remainder of the day.

This method of administration is ~rticul~rly convenient when oral loading doses which are maintained at tho~e levels are hampered by undesirable sid~ e~ect~, ye~
single, once daily dosing as of importanee (part1cularly so with the elderly or ~enile patient)O

Another potential of the patch ~ith a burstable membrane be~ween compart~ents i~ in the ca~e wherein a particular for~ulat~on ~u~t be applied ~ithin ~ ~hort time of mixing the ingredient3. In these case~, the pa~che~
are loaded with the dif~erent ingredisnts i~ dif~rent ~7!~37~

compartments, The seal betwe~n the compartments is ruptured and the contents worked together ~y the user.
The pat-h is then a~pli~.

An alternative embodiment of the patch having different ingredients in different compartments, which are to be mixed i~unediately prior to or at the time of applying the patch is the case wherein the patch as seen in Figures 17 and 18, after removal of a~ occlusive removable layer 6, folds over on itself, joining two different compartments ~ogether so that their contents may mix together. In this position the patch differs from those previously described in that in cross-section appears as though the reservoirs 8a and 8b are separated by an additional permeabl~ double membrane and adhesive layers (essentially parallel to the backing layer), The patches of the instant invention are prepared in typically known manners. Advantageously the bound~ries between compartments, when they are not burstable, are heat sealed. However, other methods will be obvious to those of ordinary skill.

The pa~ch of the instant invention can be u~d to deliver any drug to the ~kin in a controlled manner~ The only limi~ations on the drugs which are useful in ~he present invent~on are tha~ they are either (l) transdermally absorbed ~wi~h or ~ithout 3 flux enhancer) at a level ~ufficient to elicit a therap~utic sy~t~ic respon~e or (2~ elicit a therapeutlc topical respon~e. Of cour~e, they must be capable of traversing the porou~
membrane and, in appropriate ~ircum-~tances, the adhesive employed to fix ~he pa~h ~o the ~kln.

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In practicing this invention one can employ any systemically active drug which will be absorbed by the body surf~ce to which the bandage is applied, consistent ~ith their known dosages and uses. ~ course, the amount of drug necessary to obtain the desired therapeutic effect will vary depending on thé particular drug used. Suitable sys~emic drugs include, without limitation, antimicrobial :agents such as penicillin, tetracycline, oxytetracycline chlort~tracycline, chloramphenicol, and sulfonamides;
sedatives and hypnotics such as pentabarbital sodium, phenobarbital, s~cobarbital sodium, codeine, (a-bromoisovaleryl)urea, carbromal, and sodium pheno-barbital, psychic energizers such as 3-(2-aminopropyl)-indole acetate and 3-(2-aminobutyl)indole acetate;
tranquilizers such as reserpine, chlorpromazine hydro-chloride, and t~iopropazate hydrochloride; hormones such as adrenocorticos~eroids, ~or example 6q-methyl~
prednisolone; androgenic steroi-ds, for example, methyltestosterone, and fluoxymesterone; estrogenic steroids, for example estrone, 17~-estradiol and ethinyl estradiol; progesterone, and norethindrone; and thyroxine;
antipyretics such as aspirin, salicylamide, and ~odium salicylate; morphine and other narcotic a~algesics; anti-diabetics, e.g., insulin; kardiovascular agents~ e~g.
nitroglycerin, and cardiac glycosides such as digitoxin, digoxin, ouabain; antispasmodics ~uch as atropine, methscopolamine bromide~ methscopolamine bromide combined with phenobarbital; antimalarials such as an 4-amino~
quinolines, 9-amino-quinolines, and pyrimethamine: and nutri~ional agents such as vit~mins, essentia~ amino acids, and essential fats.

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Additionallyr in practicing this invention one can employ a wide Yariety of topically active drugs consistent with thei~ known dosages and uses~ Suitable drugs include, ~ithout limitation: antiperspirants~ e.g., aluminum chloride; deodorants, e.g., hexachlorophene, methylbenzethoniUm chloride; astrinqents, e.g., tannic acid; irritants, e~gO~ methyl salicylate, camphor, cantharid; keratolytics, e.g., benzoic acid, salicylic acid, resorcinol, iodochlorhydroxyquin; antifungal agents, such as tolnaftate, griseofulvin, nystatin and amphotericin; antiinflammatory agents, such as corticosteroids, e.g., hydrocortisone, hydrocortisone acetate, prednisolone, methylprednisolonel triamcinolone acetonide, fludrocortisone, flurandrenolone, flumethasone, dexamethasone sodium phosphate, bethamethasone, bethamethasone valerate, fluocinolone acetonide; fluorometholone; and pramoxine HCl; antineoplastic agents, e.g methotrexate, and antibacterial a.gents, such as bacitracin, neomycin, erythromycin, tetracycline HCl, chlortetracycline HCl, chloramphenicol, oxytetracycline, polymyxin B, nitrofuraxone, mafenide (a-amino-p-toluenesulfonamide~
hexachlorophene, benzalkonium chloride, cetalkoniwm chloride, methylbenzethonium chloride, and neomycin sulfate.

It will be appreciated, with regard to the aforesaid list of drugs the characterization of the drug as eithe2-~systemically or topicallyU ~ctive is done for purposes of convenience only. Further, a given drug can be both ~ystemically and topically active depending upon it~
manner of use.
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~2~ 37 In addition to the aforementioned drugs, simplepharmacolo~ically acceptable derivatives of the drugs, such as ethers, esters, ~ides, acetals, salts, etc., or formula~ions of these drugs, having the desired polymeric permeability or transport or transport properties can be prepared and used in practicing the invention. Drugs mentioned above can be used alone or in combination with others and each other. Of course, the derivatives should be such as to convert to the active drugs within the body through the action of body enzyme assisted transformation, pH, etc.

The above drugs and other drugs can be present in the reservoir alone or in combination fo~m with pharmaceutical carriers. The pharmaceutical carriers accsptable for the purpose of this i-nven-tion are the art known-carriers that do not adversely affect the drug, the -host, or the material comprising the drug delivery device. Suitable ~harmaceutical carriers include sterile water; saline, dextrose; dextrose in water or saline, condens~tion products of castor oil and ethylene oxide combinining about 30 to 35 moles of 0thylene oxide per mole of castor oil;
liquid glyceryl triester of a lower molecular weight fatty acid; lower alka~ols, oils such as corn oil, peanut oil, sesame o;l and ths lik~, hydrocarbons such as mineral oils and silicones, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols:
aqueous media in the presence of a suspending agent, ~or example, Rodi~n carboxyraethylcellulo~e; sodium alginate;
poly~vinylpyrrolidone); and the like, alone~ or wi~h suitable dispersing agents such as leoithin;
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polyoxyethylene stearate; and the like. The carrier may also contain adjuvants such as ?reserving, stabilizing, wettin~, emulsifying agents, and the like.

The drug can also be mixed in the reservoir with a transporting agent, that is, a material that aids or assists the drug delivery device to achieve the administration of a drug to a drug receptor, for example, by enhancing penetration through the skin. The transporting aids suitable for the purpose of the invention are the therapeutically acceptable transporting aids that do not adv~rsely affect the host, the drug, or alter or adversely affect the materials forming the drug delivery device. The transporting aids can be used alone or they can be admixed with acceptable carriers and the like. Exemplary of transporting aids include mono~alent, saturated and unsaturated aliphatic cycloal-iphatic and aromatic alcohols having 4 to 12 carbon atoms, such as hexanol, cyclohexane and the like; aliphatic, cycloaliphatic and aromatic hydrocarbons having from 5 to 12 carbon ato~s such as hexane, cyclohexane, isopropylbenzene and the like; cycloaliphatic and aromatic aldehydes and ketones having from 4 to 10 carbon atoms such as cyclohexanone; acetamide; N,N-di(l~wer) alkyl ace~amides such as N,N-diethyl acetamide, N,N-dimethyl acetamide, Clo-c2o-alkano~l-di-cl-c~-alkylamidel e.g. N,N
dimethyllauroylamide, l-C10-C20-alkylazacycloheptan-2-one, e.g. ~-n-dodecylazacycloheptan-2~on ~Azon~, Nelson) N-(2-hydroxyethyl) acet~mide, and the like; and other transporting agents such as aliphatic, cycloaliphatic and aromatic esters; N,N-di(lower) alkyl sulfoxides; essential oils; halo~enated or nitrated ~liphatic, cycloaliph~tic and aromatic hydrocarbon~;
salicylates; polyalkylene 91yc~1 8ilicat~s; ~xtures thereof; and the like.

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The amount of active agent to be incorporated in the patch to obtain the desired therapeutic e~ect will vary dependin3 upon the desired dosage, the per~eability of the rate controlling~ materials of the patch which are employed to the particular agent to be used, and the length of time the patch is to remain on the skin or body mucosa. Since this invention is designed to control drug administration ~or an extended period of time, such as 1 day or more, there is no critical upper limit on the amount ef agent incorporated therein. The lower 1imit is determined by the fact that sufficient amounts of the agent must remain in the bandage to maintain the desired dosage. In order to achieve a therapeutic affect in a human adult, the daily release dosage of atropine should be in the range of between 200 and 600 m~crograms per day~ Thus, for example, usi~g atropine and with a patch intended to remain in place for 1 week-having a release rate of 500 micrograms of atropine per day, at least 3~5 mg of atropine would be incorporated. Of course, other devices for use for different time periods such as w~ek or month are also readily made by the invention.

Nitroglycerine and arecoline are especially ~uited for use in the instant invention~

Concentrations of the drugs in the compartments are virtually unlimited since delivery rate is contr~lled by the porous membrane and adhesive layer. ~owever~ the concentration must be at least great enough ~o that the drug will leavs the vehicle once the protective layer is removad. should the amount of drug/unit area~unit time be insufficient to render an appropriate do~e of tha drug, a larger patch may be employ~d. However, it is more , ,' ` . :

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advantageous to utilize concentrations of drug suffi-ciently high so that patch size is ke?t down. Also advan-tageous are saturated systems. Most advantageous are systems capable of delivering the drug in a therapeutical-ly useful degree in an area reasonably related to the application site in view of medical, aesthetic, and patient convenience considerations.

The porous membranous materials o this invention, which may or may not be rate controlling as desired, are known in the art and can be visualized as a plurality of sponge-like fused polymer particles which provide a supporting structure having therethrough a dispersion of microscopic sized interconnecting voids or pores. The rate controlling structure~ formed from the materials can be isotropic, wherein the structure .is homogenous throughout the cr~ss-section of th-~ matrix or membrane material, or anisotropic wherein the structure is non-homogenous. These materials are commercially available and can be made by a multitude of dif~erent methods, e.g., etched nuclear track, and materials employed, e.g., polyelectrolyte, ion exchange polymers, a~
described in R. E. ~esting, Synthetic Polymer Membranes, McGraw Hill, Chapter~ ~ and 5, 1971; J. D. Ferry, Vltrafiltration Membrane , Chemical ~eYiew, Vol. 18, Pag~
373, 19840 Materials possessing from 5 percent to 95 percent voids and having an efective pore si~e of from about 10 angstroms to about 100 microns are particularly suitably employed in the practic~ of thi~ invention.
Materials with pore ~îze~ ~ignificantly below 50 ang~troms can be considered to be molecular diffusion type ~e~brane~
and matrices. ~n order o obtain the mo~ advanta~eou~
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results, the materials should be formed into structures with the desired morphology in accordance with methods known to those skilled in the art to ac~ieve the desired r~lease rate of drug. Additionally, the ma~erial must have the appropriate chemical resistance to the drug used and be non-toxic when used as an element of the patch of the invention.

Materials useful in forming the porous rate controlling materials used in this invention include, but are not limited to the following:

Polycarbonates, i.e~, linear polyesters of carbonic acids in which carbonate groups recur in the polymer chain, by phosgenation of di~ydroxy aromatics such as bisphenol A. Such material are sold under ~he trade designationLexa ~ by the General Electric Company.

Polyvinylchlorides; one such material is sold under the trade designationGeon~ 121 by B. G. Goodrich Che~ical Company.

Polyamides such as polyhexamethylene adip~mide an~
other such polyamides popularly known as ~nylon~. One particularly advantageous material is that sold under the trade name NOME ~ by E. I. DuPont de Ne~ours ~ Co.

Acrylate copolymers~ such as that sold under the trade de~ignaticnD~NEL~ are formed of polyvinylehloride (60 percent) and acrylonitril~ (40 percent), ~tyrene-acrylic acid copolymer~, and the like.

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- : . . : :; -', ", ,, ~ ~ 7 Polysulfones such as those of the type characterized by diphenylene suIfone groups in the linear chain thereof are useful. Such materials are available from Union Carbide Corporation under the trade designation P-1700.

Halogenated polymers such as polyvinylidene fluo~ide sold under the trade designation Kyna ~ by Pennwalt Chemical Corporation, polyvinylfluoride sold under the trade name Tedlar~by E.I. DuPont de Nemours & Co., and the polyfluorohalocarbon sold under the trade name Aclar~ by Allied Chemical ~orporation.

Polychlorethers such as that sola under the trade name Penton~ by Hercules Incorporated, and other such thermoplastic polyethers.

Acetal polymers such as the polyformaldehyde sold under the trade name Delrin~ by E.I. DuPont de Nemours Co., and the like.

Acrylic resins such as polyacrylonltrile polymethyl methacrylate, poly-n-butyl methacrylate and the like.

Other polymers such as polyurethanes, polyimides, polybenzimidazoles, polyvinyl acetate, aromatic and aliphatic, polyethers, cellulose esters, e.g., cellulose triacetate; cellulose; colledion (cellulose nitrate with 11 %
nitrogen); epoxy resins; polyolefins, e.g. polyethylene or polypropylene; porous rubber; cross linked poly(ethylene oxide); cross-linked polyvinylpyrrolidone; cross-linked poly(vinyl alcohol); polyelectrolyte structures formed of two ionically associated polymers of the type as set forth ~, ,, i:
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in U.S. Pat. Nos. 3,549,016 and 3,546,142; derivatives of polystyrene such as poly(sodium styrenesul~onate) and poly(vinylbenzyltrimethyl-ammonium chloride); poly(hydroxy-ethylmethacrylate); poly(isobutylvinyl ether), and the like, may also be utilized. A large number of copolymers which can be fonmed by reacting various proportions o monomers from the aforesaid list of polymers are also useful ~or preparing rate controlling structures useful in the invention.

While the non-rate controlling walls of the reservoir can be of any convenient thickness, usually they have a thickness of from 0.01 to 7 millimeters. The rate controlling membranes an have varying thickness depending upon the nature of the membrane, its porosity and the number of membranes used in combination. Typically, a thickness of ~rom 20 to 200 microns is em~loyed.

It will, of course, be appreciated that the pressure-sensitive adhesive surface need not form a continuous layer on the subject bandage. Particularly in the case of a bandage having a distinct reservoir layer, equally advantageous results are obtained by providing an annular surface of adhesive around the periphery of th~
bandage face. In this manner a liquid t~ght adhesive ~eal between the bandage asld the patient ' s 5kin or mucosa is maintained, and at the same ti~e, drug may be directly absorbed by the skin from the exposed surface of ~he drug re~ervoir layer without first migrating through an adhesi~le layer .

~''' ~ `"' ' Any of the well known dermatol5gically acceptabls pressure-sen5itive adhesives can be used in practicing this invention. Exemplary adhesives include acrylic or metha~
crylic resins such as polymers of esters of acrylic or metha-crylic acid with alcohols such as n-butanol, n-pentanol, iso-pentanol, 2-methyl butanol, l-methyl butanol, l-methyl pentanol, 2-methyl pentanol, 3-methyl pentanol, 2-ethyl butanol, isooctanol, n-decanol, or n dodecanol, alone or copolymerized with ethylene groups containing unsaturated monomers ~uch as acrylic acid, methacrylic acid, acrylamide, methacrylamide, N-alkoxymethyl acrylamides, N-alkoxymethyl methacrylamides, N-tert.butylacrylamide, itaconic acid, vinylacetate, N-branched alkyl maleamic acids wherein the alkyl group has 10 to 24 carbon atoms, glycol diacrylates, or mixtures of these; natural or synthetic rubbers such as styrenebutadiene, butylether, neoprene, polyisobutylene, polybutadiene, and- polyisoprene; polyvinylacetate;
ureaformaldehyde resin~; phenolformaldehyde ~esins;
resorcinol fonnaldehyde resins, cellulose derivatives such as ethyl cellulose, methyl cellulose, nitrocellulose, cellulose acetatebutyrate, and carboxymethyl cellulose;
and natural gums such as guar, acacia, pectins, starch, dextrin, albumin, gelatin, casein, etc. The adhesives may be compounded with thickening agents and stabilizers as is well known in the art.

Various occlusive and non-occlusive, flexible or non-1exible bac~ing members can b8 used in the adhesive patch of the invention. Suitable backing~ include cellulose acetate, ethylcellulose, plasticized vinylacetate-vinylchloride copolymer~p polyethyl~ne terephthal~te, nylon, polyethylene~ polypropylene, ' ~ ' '.,., ~ , ;~
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~7~17 polyvinylidenechloride, paper, cloth, and aluminum foil.
Preferably, a flexible occlusive backing is employed to conform to the shape of the body member to which the adhesive tape is applied and to enhance a~ministration of the agent to the skin~

To prevent passage of the drug away from the exposed surface of the pressure-sensitive adhesive prior to use, the adhesive surface of the tape generally is covered with a protective release film or foil such as waxed paper.
~lternatively, the exposed rear surface of the backing member can be coated with a low~adhesion adhesive and the bandage rolled about itself. To enhance stability of the active compounds, the therapeutic bandage is usually hermetically sealed between appropriate layer such as polyethylene terephthalate films under an inert atmosphere, such as ~aseous nitrogen.

To use the adhesive patch of the invent.ion, wherein the drug is topical, it is applied directly to the area of skin to be treated, to release a therapeutically effective amount of the agent to the affected area. For administration of systemic drugs the bandage ca be applied to any area of the patient9s skin, with the lower back, chest and buttocks being the areas of choice. In like manner, the patch can be applied to the mucosa of the mouth, for example, by application to the palate or ~he buccal mucosa, to obtain absorption of the drug ~y the oral mucosa. Similarly, where desired and accessable, the patch can be appli~d to other mucou~ ~embrane~.

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The following examples more specifically describe the invention; however, the ~cope o the invention is not limited to the embodiments set forth therein.

ExamE le 1 A transdermal system according to the invention is manufactured as follows:

A drug reservoir formulati~n is prepared by dispersing nitroglycerin 10% on lacto~e in silicon fluid containing colloidal silica as a suspension stabilizer, the final concentration of nitroglycerin in the fomulation being adjusted to 5~ wtw.

A silicon ba~ed contact adhesive solutrDn in hexane is cast-onto a 100 micron thick notched film-of polyviny}chloride (PVC). After drying of the adhesive the adhesive side of this assembly is laminated to a S0 micron thick membrane of ethylene-vinyl acetate (EVA) copoly~ler leaving a strip at one side free of adhesive.

Three 1 g portions of the nitroglycerin suspension are placed beside each other on the EVA copoly~er side of the de~eribed lami~ate and a 60 micron thi~k backing film of aluminized polyethylene terephthalate with an E~ heat sealable coating is laid over the portions of drug reserYoir formula~ion and heat sealed at the periphery and between the individual portions as shown in Fi~ure 8.

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The fini5hed sy~tem havin~ 3 chambers ~ith a ~ontact area of 20cm2 for each of the 1 9 reservoir portions i~
punched as shown in Figures 3, 9, and 11. Fig. 10 shows the ~penin~ tab on one side o~ the system which is left free of adhesive.

The system ~as an an active drug releasing surface of 60cm2 and delivers 3~mg of nitroglycerin within 24 hours through intact human skin in vivo.

Example 2: A transdermal system comprising 2 different actlve drug formulations is prepared as follows:

A drug reservoir formulation is prepared by dispersing nitroglycer-in 18 % on lactose in paraffin fluld with the additlon of colloidal silica as stablllzer. The nltroglycerin concentration is adJusted to 5 % wlw.

A drug reservoir formulation using viscous paraf~in is pr0pared in the same manner.

A poly~sobutylene adhesive solution i9 applied to a siliconized polyester film and laminated with a 50 ~m ethylene-vinyl acetate (EVA) copolymer film, leaving a strip on one side free of adhesive.

One 750 mg portlon of each of the two drug reservoir formulations is applied beside each other to the EVA copolymer side of the lamlnate, covered with a heat-sealable polyester film and beat sealed at the periphery and between the individual portions to form a system having 2 chambers each with an area of 15 cm2.

The punched system has an actlve drug releaslng surface area of 30 cm2 with a different rate of drug release from each chamber.

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Example 3: A transdermal system comprising 2 different active drugs is prepared as follows:

A solution of 5 % w/w lynestrenol in ethanol is thickened to a gel with hydroxypropyl cellulose.

A gel of 1 ~0 w/w mestranol in ethanol is prepared in the same manner. A transdermal system comprising the films and the adhesive of Example 2 is prepared by filling one chamber having an area of 10 cmZ with 200 mg of lynestrol gel and a second chamber having an area of 5 cmZ with 100 mg of mestranol gel.

The punched system has 2 chambers differing in size and havlng a total surface area of 15 cm2. The system delivers 2 different active drugs to the skln.

Example 4: A transdermal system with accelerated onset of action is prepared as follows:

A drug reservoir formulation as described ln Example 1 is prepared.
A second drug reservoir formulatlon L~ prepared in the same manner, except that 5 % wlw of the silicone oil is replared by dimethylsulfox-ide.

Using the idantical films and adhesives as described in Example 1, a transdermal system is prepared that comprises 4 chambers each having sn area of 10 cm2 and each containing 500 mg of drug reservoir formulation. Three chambers are filled with the first drug reservoir formulation, the fourth containing the second fo~mulation with dimethylsulfoxide.

The punched system having a total surface area of 40 cm2 has initially a higher rate of release of active drug owing to the permeation-promo~ing property of the dimethylsulfoxide, and later a constant rate of release at a lower level.

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Claims (13)

WHAT IS CLAIMED IS:

1. In a transdermal or dermal patch for administering a controlled amount of a drug to the skin or mucous membranes comprising, in sequence, (1) a backing layer which is not permeable to an active ingredient, (2) a first membranous layer permeable to said active ingredient, said first membranous layer and said backing layer being sealed together so a to define an enclosure for containing an active ingredient, (3) an active ingredient contained within said enclosure, (4) an adhesive layer on said first membranous layer and (5) a first removeable protective layer on said adhesive layer, the improvement which comprises subdividing said enclosure into at least two compartments, each compartment capable of containing the same or different active ingredient or formulation thereof therein.

2. The patch of claim 1 wherein each compartment is not greater than 20 cm2 in area.

3. The patch of claim 1 wherein aech compartment is not greater than 13.3 cm2.

4. The patch of claim 1 wherein the maximum distance from the center of gravity of a compartment and a boundary of said compartment is 2.70 cm.

5. The patch of claim 1 wherein said maximum distance is 1.78 cm.

6. The patch of claim 1 wherein the perimeter of a compart-ment is not greater than 4.04 times the square root of that compartment area.

7. The patch of claim 1 wherein said sealed enclosure is circular and the common border between two compartments is a radius of said enclosure.

8. The patch of claim 1 wherein said enclosure has a rectangular-like shape such that said enclosure has a perimeter defined by a pair of parallel lines which are connected to each other via arcuate lines, said enclosure being subdivided into said compartments by a seal sub-stantially perpendicular to said straight, parallel lines.

9. The patch of claim 1 wherein at least one compartment contains therein a drug formulation which is different than that in at least one other compartment of said patch.

10. The patch according to claim 9 wherein at least one compartment contains drug formulations of different drugs.

11. The patch according to claim 9 wherein at least one compartment contains a drug formulation admixed with a flux-entrancer.

12. The patch of claim 1 wherein said active agents are nitroglycerine, scopolamine, oestradiol or arecoline.

13. The patch of claim 12 wherein at least one compartment contains drug formulations having nitroglycerine in different concentrations.

FO 7.4/RS/hpw*